KAP Degradation by Calpain Is Associated with CK2 Phosphorylation and Provides a Novel Mechanism for Cyclosporine A-Induced Proximal Tubule Injury

The use of cyclosporine A (CsA) is limited by its severe nephrotoxicity that includes reversible vasoconstrictor effects and proximal tubule cell injury, the latter associated whith chronic kidney disease progression. The mechanisms of CsA-induced tubular injury, mainly on the S3 segment, have not been completely elucidated. Kidney androgen-regulated protein (KAP) is exclusively expressed in kidney proximal tubule cells, interacts with the CsA-binding protein cyclophilin B and its expression diminishes in kidneys of CsA-treated mice. Since we reported that KAP protects against CsA toxicity in cultured proximal tubule cells, we hypothesized that low KAP levels found in kidneys of CsA-treated mice might correlate with proximal tubule cell injury. To test this hypothesis, we used KAP Tg mice developed in our laboratory and showed that these mice are more resistant to CsA-induced tubular injury than control littermates. Furthermore, we found that calpain, which was activated by CsA in cell cultures and kidney, is involved in KAP degradation and observed that phosphorylation of serine and threonine residues found in KAP PEST sequences by protein kinase CK2 enhances KAP degradation by calpain. Moreover, we also observed that CK2 inhibition protected against CsA-induced cytotoxicity. These findings point to a novel mechanism for CsA-induced kidney toxicity that might be useful in developing therapeutic strategies aimed at preventing tubular cell damage while maintaining the immunosuppressive effects of CsA

Unsaturated shear strength of a silty sand

Series of single stage, consolidated drained direct shear tests under different net normal stresses and matric suctions were carried out to evaluate the unsaturated shear strength behavior of a silty sand. A back pressure shear box was used to measure and control pore-air and pore-water pressures. The experimental data show that matric suction increases shear strength of the soil significantly following a highly non-linear relationship. An increase in net normal stress results in a higher shear strength and the shearing behavior changes gradually from a peak shear strength followed by a strain-softening behavior to a strain-hardening behavior. A comparison between experimental shear strength measurements and predicted unsaturated shear strength values was made and the results are presented in the paper

Toxic nephropathy: Environmental chemicals

The kidney is the target of numerous xenobiotic toxicants, including environmental chemicals. Anatomical, physiological, and biochemical features of the kidney make it particularly sensitive to many environmental compounds. Factors contributing to the sensitivity of the kidney include: large blood flow, the presence of a variety of xenobiotic transporters and metabolizing enzymes, and concentration of solutes during urine production. In many cases, the conjugation of environmental chemicals to glutathione and/or cysteine targets these chemicals to the kidney where inhibition of renal function occurs through a variety of mechanisms. For example, heavy metals such as mercury and cadmium target the kidney after glutathione/cysteine conjugation. Trichloroethlene and bromobenzene are metabolized and conjugated to glutathione in the liver before renal uptake and toxicity. In contrast, renal injury produced by chloroform and aristolochic acids is dependent on renal cytochrome P450 metabolism to toxic metabolites. Other compounds, such as paraquat or diquat, damage the kidney via the production of reactive oxygen species. Finally, the low solubility of ethylene glycol metabolites causes crystal formation within the tubular lumen and nephrotoxicity. This chapter explores mechanisms of nephrotoxicity by environmental chemicals, using these example compounds. What remains to be accomplished and by far the most difficult process is the elucidation of the detailed mechanisms of tubular cell injury after toxicant uptake and metabolism. The large number of individuals experiencing a decline in renal function with age makes the search for these mechanisms very compelling

Effect of rising water table in an unsaturated slope

Recently, climatic changes have caused more extreme weather conditions such as heavy rain falls and droughts. Therefore, climatic changes are expected to produce increased variations in infiltration characteristics and positions of water table in slopes. A physical slope model has been developed to study the effects of climatic changes in an unsaturated slope. The effect of rising water table in an unsaturated slope was investigated experimentally in the physical slope model. In addition, finite element analyses were carried out to simulate infiltration in slopes under steady-state and transient conditions. A comparison between the results of laboratory model measurements and numerical analyses shows good agreement despite the complex unsaturated soil conditions. Both, experimental data and numerical analyses demonstrate a delayed response in pore-water pressure in the unsaturated zone due to the rising of water table. A conceptual framework is presented to describe the physically possible lower and upper limits of pore-water pressures in a slope resulting from the rise in water table.Accepted versio